PROJECT SUMMARY Dysregulation of the intestinal microbiota and the human immune system is thought to contribute to chronic diseases such as inflammatory bowel disease, heart disease, diabetes, and cancer. A better understanding of the interactions between the microbiota and the host immune system should highlight novel therapeutic strategies for these chronic diseases, including therapies directly targeting the microbiota rather than the host. Recent studies have shown that a subset of the microbiota colonizes healthy human, non-human primate, and mouse lymphoid tissues. These bacteria, termed lymphoid tissue-resident commensals or LRCs, elicit unique innate immune responses, and protect against intestinal inflammation. However, the molecular basis of LRC colonization of lymphoid tissues, and LRC-elicited innate immune responses, remains unclear. Preliminary data in this proposal suggests that LRCs may suppress host nitric oxide responses in dendritic cells using a conserved bacterial arginase. Aim 1 will utilize in vitro and in vivo models of LRC colonization to interrogate the interaction between LRC arginases and the host innate immune system. Additionally, preliminary studies suggest that host iron transport may actively contribute to both LRC colonization and intestinal inflammation. Aim 2 will utilize in vitro and in vivo models of LRC colonization, along with novel murine models with modified iron transport, to investigate the connection between LRC colonization, host iron transport, and inflammation. Collectively, these two aims will crucially define the molecular basis by which LRCs colonize mammalian hosts and modulate intestinal inflammation.